BMS-354825

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BMS-354825 Chemical information IUPAC Nomenclature N-(2-Chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide Chemical Formula C22H26ClN7O2S Molecular Weight 488.01 g/mol Solubility DMSO Clinical information Clinical Usage Chronic myelogenous leukemia (CML) anticancer drug[1][2] Mechanism of Action BCR-ABL inhibitor, IC50 < 1.0 nM Src inhibitor, IC50 = 0.50 nM Lck inhibitor, IC50 = 0.40 nM Yes inhibitor, IC50 = 0.50 nM Known Side Effects Minimal side-effects[1] Route of Administration Oral[1][2] Intravenous[1] Legal Status Approved for clinical usage by the UNSC Medical Corps Marketed by Acumen Science Laboratories Pharmacokinetic information Bioavailability High Elimination Half-Life High (Plasma t1/2 = 3.1-3.3 hours)[1]

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BMS-354825, IUPAC name N-(2-Chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, is a small-molecule chemical inhibitor of the oncogenic BCR-ABL fusion kinase (Breakpoint cluster region-Abelson kinase) and of Src family kinases (Src, Lck, and Yes). BMS-354825 has an IC₅₀ < 1.0 nM against BCR-ABL, IC₅₀ = 0.40 nM against Lck, and IC₅₀ = 0.50 nM against Src and Yes.^[1]

It is a highly potent of both BCR-ABL and Src kinases in sub-nanomolar concentrations, and serves as a polypharmacological dual inhibitor, thus relaxing its structural binding specificity to ABL and increasing tolerance to point amino acid mutations that would otherwise confer resistance to other kinase inhibitors; BMS-354825's characteristics allow it to override the M244V, G250E, Q252H, Q252R, Y253F, Y253H, E255K, E255V, F317L, M351T, E355G, F359V, H396R, and F486S mutations in ABL that otherwise confer resistance to imantinib, thus demonstrating its clinical relevance.^[2]

[edit] References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4 1.5} Lombardo et. al (2004). Discovery of N-(2-Chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a Dual Src/Abl Kinase Inhibitor with Potent Antitumor Activity in Preclinical Assays. Journal of Medicinal Chemistry (27): 6658-6661.
2. ↑ ^{2.0 2.1 2.2} Shah et. al (2004). Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor. Science (305): 399-401.

Anticancer Drugs (Acumen Science Laboratories): Chemical Biology and Oncology
A-83-01 (Colon Cancer) · Bicuculline (Brain Cancer) · BMS-354825 (Chronic Myeloid Leukemia) · Dorsomorphin/LDN-193189 (Lung Cancer) · Cyclopamine/Robotnikinin/SANT1 (Skin, Brain, Prostate, and Colon Cancers) · LY165163 (Brain Cancer) · PK115-584 (Colon and Brain Cancer)
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Chemical Biology: Small-Molecule Control of Biological Systems (RelentlessRecusant)
Biological Targets		Compound Names
Receptor Tyrosine Kinases		A-83-01 (TGFβ/Activin) · BPIQ-II (EGFR) · Dorsomorphin/LDN-193189 (TGFβ/BMP) · SU5402 (FGFR)
Signaling Kinases		A-769662 (AMPK) · BMS-354825 (BCR-ABL, Src)· BIO-Acetoxime (GSK3) · CHIR99021 (GSK3) · GO 6976 (PKC) · IMD-0354 (IκBa) · PD184352 (MAPK) · SB203580 (MAPK) · Y-27632 (ROCK)
G Protein-Coupled Receptor		(+)-WIN-55212 (CB1/CB2) · ±-Sulpride (D2) · A 841720 (mGluR1) · BP-554 (5-HT1A) · Hh-Ag1.5 (Smo) · Cyclopamine/KAAD-Cyclopamine (Smo) · SANT1 (Smo) · SB-277011 (D3)
Ion Channels		BAY K8644 (Cav1.2) · Bicuculline (GABAAR) · Cymarin (Na+/H+) · G-strophanthin (Na+/H+) · L-AP4 (Na+/H+) · Oxcarbazepine (Na+) · Resiniferatoxin (TRPV1) · Sarmentogenin (Na+/H+) · Theanine (AMPAR, NMDAR)
Transporters		O-1783 (DAT) · WF-23 (DAT, SERT)
Nuclear Receptor		All-trans retinoic acid (RAR/RXR) · GW501516 (PPARδ) · RU-486 (Nr3c1, Nr3c3)
Protein Phosphatases		Endothall (PP2A)
Polypharmacological		Phosphoserine (mGluR4) · PK115-584 (Tcf4/β-catenin, PKC) · Pluripotin · Reversine
Other		2C-E (DAT) · 4-methoxyphenyl-HTI-286 (α/β-tubulin) · Compound E/DAPT (presenilin-1) · D-cysteine · D-phenylalanine · Flurbiprofen (COX) · JZL184 (MAGL) · QS11 (RAFGAP1) · RO-28-1675 (glucokinase) · Robotnikinin (Shh) · Selegiline (MAOB)
Uncharacterized		Neuropathiazol
Libraries		Kinase Inhibitor Library
Publications
Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype (Rubin et. al, 2590. Nature Medicine)
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